The enzyme testosterone 5-α-reductase is known to convert testosterone to dihydrotestosterone, DHT in the human body. DHT has been implicated in causing enlargement of the prostate and benign prostatic hyperplasia (BPH), which leads to malignant conditions such as prostate cancer. Accordingly, it is desirable to inhibit the action of testosterone 5-α-reductase, and a number of 4-aza-steroids have been reported to be active in this respect. In particular, two 4-aza-steroids 5-α-reductase inhibitors, namely Finasteride (Proscar™) and Dutasteride (Avodart™) have reached the market for the treatment of BPH. A major advantage of these compounds is that they do not bind with androgen receptor sites. Specifically for Finasteride, it doesn't possess androgenic, anti-androgenic, or other steroid hormone-related properties. Therefore, Finasteride can lower the DHT level in humans without interfering with the testosterone levels. Finasteride has also been studied on hair growth, hair cycle stage, and serum testosterone and dihydrotestosterone, and it was found that Finasteride increased hair weight. Finasteride, marketed with the trade name Propecia™, is the first and only drug to date to be approved by the FDA for the treatment of male pattern hair loss on the vertes (top of head) and anterior mid-scalp area (middle front of head).
Finasteride and Dutasteride may be prepared by various known methods that involve the steps of converting the 17β-carboxyl group into t-butylcarbamoyl and 2,5-bis(trifluoromethyl)phenylcarbamoyl groups respectively and introducing the 1,2-double bond by dehydrogenation.
Numerous methods have been disclosed for converting the 17β-carboxyl group to an amide. For instance, U.S. Pat. No. 4,760,071 discloses a method of preparing a 17β-t-butylcarbamoyl derivative by converting the 17β-carboxyl group into a pyridylthio ester which is subsequently reacted with the amine. However, this method requires the use of expensive 2,2′-dithiopyridine.
US Patent Application 2005/0059692 A1 discloses a process for synthesizing Dutasteride by reacting the 17β-carboximide group with 2-iodo-1,4-bis(trifluoromethyl)benzene. However, this method uses insoluble copper halide that requires repeated washing and filtering to remove.
U.S. Pat. No. 5,670,643 offers a method to convert the 17β-carboxyl group into an acid chloride and reacting the acid chloride with t-butylamine. However, this method uses toxic thionyl chloride, which is difficult to handle, and the product is difficult to purify.
U.S. Pat. Nos. 5,468,860 and 5,652,365 and EP patent 599,376 disclose a method of reacting an organomagnesium halide with t-butylamine to obtain a t-butylaminomagnesium halide, and then reacting the t-butylaminomagnesium halide with a 17β-carboalkoxy compound. However, this method suffers from the disadvantage that the organomagnesium halide is expensive and moisture-sensitive.
EP patent 271,200 describes a method to convert the 17β-carboxyl group into a hydroxybenzothiazolyl ester or imidazolide which is subsequently reacted with t-butylamine. However, this method has the deficiency that the reaction yields a product of low purity.
There are also several synthetic methods reported in the prior art for introducing a 1,2-double bond into 4-azasteroids. For example, U.S. Pat. No. 4,760,071 discloses that dehydrogenation is carred out using benzeneseleninic anhydride in refluxing chlorobenzene. However, benzeneseleninic acid anhydride is a highly toxic material and is unsuitable for industrial production.
U.S. Pat. No. 5,116,983 teaches a method whereby the 1,2-double bond was introduced by refluxing with 2,3-dichloro-5,6-dicyano-4-benzoquinone (DDQ) and bis(trimethsilyl)-trifluoroacetamide (BSTFA) in dioxane. The disadvantages of these procedures include the facts that BSTFA is very expensive and DDQ is highly toxic. The latter deficiency complicates the purification to obtain a pharmaceutically acceptable product.
U.S. Pat. No. 5,021,575 discloses a four step process comprising:                a) reacting a 17β-substituted-3-oxo-4-azasteroid with oxalyl chloride;        b) monobrominating the oxalylated intermediate at the 2-position;        c) reacting the brominated product with ethylenediamine or 2-(N-methylamino)ethanol to produce α- and β-2-monobrominated isomers; followed by        d) dehydrobromination of the product of (c) which results in the introduction of a double bond at the 1,2-position.However, this process suffers from various disadvantages including the fact that the monobromination reaction (b) must be performed at a very low temperature (−70° C. in example 1) and with very gradual addition of a stoichiometrically precise quantity of bromine to prevent contamination of the product due to undesired reaction by-products. The very low temperatures and slow addition of bromine required in this step reduce the utility of the process for large scale production.        
WO 2005/066195 discloses a process comprising sulfenylation, oxidation and elimination to introduce the 1,2-double bond. However, the sulfenylation step requires a strong base and harsh reaction conditions (refluxing with a strong base in tetrahydrofuran for more than 16 hours), which may cause decomposition and epimerization.
Accordingly, there is a need to develop improved methods for preparing the amide group from 17β-carboxyl group and introducing a 1,2-double bond into a 3-oxo-4-aza-steroid.